Design, Synthesis, and invitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody-Drug Conjugates

A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. approximate to 4). These...

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Published inChemMedChem Vol. 13; no. 8; pp. 790 - 794
Main Authors Chen, Bo, Gianolio, Diego A., Stefano, James E., Manning, Charlene M., Gregory, Richard C., Busch, Michelle M., Brondyk, William H., Miller, Robert J., Dhal, Pradeep K.
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 23.04.2018
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
trastuzumab
polyethylene glycol
EFFICACY
antibody-drug conjugates
CANCER
CHALLENGES
multivalent drug linkers
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Summary:A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. approximate to 4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS. Using this approach, ADCs with significantly lower aggregation and higher DAR than those of conventional drug linker design were obtained with highly hydrophobic cytotoxic agents such as monomethyldolastatin10 (MMAD). The invitro potencies of the MDL-derived conjugates matched that of ADCs of similar DAR with conventional linkers, and the potency increased proportionally with drug loading. This approach may provide a means to prepare highly potent ADCs from a broader range of drugs, including those with lower cytotoxicity or poor solubility, which otherwise limits their use for antibody-drug conjugates. This may also provide a means to further improve the potency achievable with cytotoxins currently used in ADCs.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700722